Cadmium (Cd2+) poisoning is a serious health threat due to increased level of environmental pollution and lack of effective therapy. An extremely long biological half-life of Cd2+ in the human body leads to a persistent and cumulative effect. Chronic exposure to Cd2+ causes disorders of the nervous, renal, skeletal, vascular, and respiratory systems. A common pathophysiological feature of these seemingly unrelated diseases is imbalanced protein homeostasis (proteostasis). Evidence reported from our laboratory, as well as others, suggests that Cd2+ prevents the degradation of ubiquitinated proteins in human cells, and the cytotoxicity of Cd2+ can be alleviated by increasing the degrading capacity of the ubiquitin proteasome pathway in cells. However, Cd2+ does not affect proteasome activity directly. Why ubiquitinated proteins cannot be degraded in Cd2+ treated cells remains as a critical open question. Valosin-containing protein (VCP/p97), a molecular chaperone, lies at the heart of proteostasis to unfold ubiquitinated proteins for proteasomal degradation. A structural Zinc (Zn2+) located in the center pore of VCP is essential for ubiquitinated protein degradation. Since Cd2+ can substitute for Zn2+ in some proteins to change protein structure and protein function, we hypothesize that the replacement of the structural Zn2+ by Cd2+ results in loss of VCP function, and this leads to a reduction in ubiquitinated protein degradation. We propose to examine the ATPase activity and hexamer structure, two essential features of VCP in mediating protein degradation, as well as the biological actions of Cd2+-containing VCP, in an effort to understand the loss of functional activity. Our long-term goal is to define the biochemical basis for the disturbance of proteostasis underlying the protein misfolding induced by heavy metal ions. We believe these studies will contribute to a better understanding of the pathogenesis of Cd2+-associated diseases and advance the development of preventive and/or therapeutic strategies for these disorders. 1